1-(5-Carboxyindol-1-yl)propan-2-one Inhibitors of Human Cytosolic Phospholipase A₂α with Reduced Lipophilicity: Synthesis, Biological Activity, Metabolic Stability, Solubility, Bioavailability, And Topical in Vivo Activity

Abstract

Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent inhibitors of human cytosolic phospholipase A(2)alpha (cPLA(2)alpha). In continuation of our attempts to develop clinical active cPLA(2)alpha inhibitors, a series of structurally related indole-5-carboxylic acids with reduced lipophilicity was synthesized and tested for cPLA(2)alpha-inhibitory potency. Furthermore, the thermodynamic solubility of these compounds and their metabolic stability in rat liver microsomes were evaluated. With an IC(50) of 0.012 microM against the isolated enzyme, compound 36 was one of the most potent cPLA(2)alpha inhibitors that emerged during the structure-activity relationship study. Concomitantly, 36 possessed the highest water solubility (212 microg/mL at pH 7.4) of all new target compounds. Despite these favorable properties, peroral application of 36 (100 mg/kg) in mice only led to low concentrations of the substance in blood plasma. A very high plasma clearance was observed after intravenous administration of 36 (10 mg/kg). However, in a topical murine model of contact dermatitis, 36 showed a pronounced anti-inflammatory in vivo activity.

Involvement of microsomal NADPH‐cytochrome P450 reductase in metabolic reduction of drug ketones

“…This can be explained by the fact that in these experiments [7] the concentration of the microsomes was about 14-fold higher than in the present case. Under the conditions applied, haloperidol was metabolized by S9 fractions, isolated microsomes as well as cytosol only to a minor extent.…”

“…In past years, 1-heteroarylpropan-2-one derivatives were developed as inhibitors of cytosolic phospholipase A 2 α and fatty acid amide hydrolase, two enzymes involved in inflammatory processes [7,8]. Because the carbonyl group of such compounds is readily reduced to an alcohol in rat liver homogenate in vitro as well as in mice in vivo resulting in a loss of their inhibitory potency [7], our interest was focused on this metabolic reaction.…”

“…Because the carbonyl group of such compounds is readily reduced to an alcohol in rat liver homogenate in vitro as well as in mice in vivo resulting in a loss of their inhibitory potency [7], our interest was focused on this metabolic reaction. Recently, it was found that in a mixture of human recombinant CYP enzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4) and NADPH-cytochrome P450 reductase, the latterenzyme was responsible for the observed pronounced reduction of 1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5) to 1-[2-hydroxy-3-(4-phenoxyphenoxy)propyl]indole-5-carboxylic acid (6) (Figure 1) [9].…”

Determination of arachidonic acid by on-line solid-phase extraction HPLC with UV detection for screening of cytosolic phospholipase A2α inhibitors

“…Additionally, three cPLA 2 ␣ inhibitors with indole-5-carboxylic acid scaffold developed in our group [33][34][35] were evaluated. The results are shown in Table 1.…”

The Application of Rational Design on Phospholipase A2 Inhibitors

“…Thus, the inhibition of the enzyme has attracted the interest of many researchers. Some of the most potent inhibitors of the GIVA cPLA 2 include indole [107][108][109][110][111], pyrrolidine [112][113][114][115], propan-2-one [116][117][118][119][120][121] and 2-oxoamide scaffolds [36][37][38][39][40][41]. Representative structures of inhibitors are shown in Fig.…”